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A recent study helps uncover the mechanisms involved in multisystem inflammatory syndrome in children following SARS-CoV-2 infection. SDI Productions/Getty Images
  • Researchers from the Mount Sinai Health System, NY, present the first genome-wide study to investigate the cause of a rare but severe inflammatory syndrome in children following SARS-CoV-2 infection.
  • RNA sequencing of blood samples revealed that certain cells of the immune system were at lower levels in children who developed multisystem inflammatory syndrome after SARS-CoV-2 infection.
  • The findings may provide scientists with a new pathway toward the treatment of multisystem inflammatory syndrome in children (MIS-C).

All data and statistics are based on publicly available data at the time of publication. Some information may be out of date.

In a recent study, scientists sequenced RNA in blood samples from people with MIS-C and participants without the condition. The findings appear in Nature Communications.

The results indicate that lower levels of specific types of natural killer (NK) cells and “exhausted cytotoxic T cells” may be key to MIS-C. NK cells are responsible for attacking and killing viral cells.

Exposing these cytotoxic T cells to a pathogen for an extended duration causes them to become “exhausted.” In this state, they are less effective in destroying pathogens and can no longer proliferate.

Dr. Noam D Beckmann, one of the corresponding authors of the study, told Medical News Today that “[f]ollow-up studies could identify drug targets that could prevent COVID-19 from progressing into MIS-C.”

“[A]s this was and remained a major disease related to the ongoing pandemic, we thought it would be essential to investigate its etiology,” he added.

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MIS-C, also known as pediatric inflammatory multisystem syndrome (PIMS), was initially named Kawasaki-like disease. It is a dangerous but rare condition, affecting an estimated 11.4 per 100,000 people younger than 20 years. By June 2021, there had been 4,404 reported cases in the United States.

MIS-C involves pain, fever, and inflammation in different parts of the body, including the heart, lungs, brain, eyes, skin, and gastrointestinal organs.

Although scientists have suggested that the syndrome is likely to be an autoimmune condition, they do not understand the exact mechanisms involved. Studying it is challenging because it is rare.

In the recent study, the researchers found reduced production, or downregulation, of both NK cells and exhausted T cells among those with MIS-C following a SARS-CoV-2 infection.

Specifically, they noted the impact of a subset of T cells called cytotoxic T cells, or CD8+ T cells. These cells play an important role in defending against pathogens, including viruses.

The researchers further explored the pathway and found that NK cells and CD8+ T cells regulate each other. They showed that depletion of NK cells disrupts CD8+ T-cell exhaustion.

As the authors explain, “Disruption in CD8+ T-cell exhaustion can lead to severe and even fatal T-cell immunopathology after viral infection, whereas its presence can improve inflammatory disease symptoms.”

The extensive gene expression study identified nine key regulators associated with the cytotoxic cells. The expression of these regulators is generally high in these CD8+ T cells, but they are downregulated in children with MIS-C.

Among the regulators, the researchers deemed TBX21 to be particularly important because it is involved in the differentiation of exhausted cytotoxic T cells. This regulator might serve as an essential therapeutic target in MIS-C following COVID-19.

Dr. Danelle Fisher, FAAP, a pediatrician and chair of pediatrics at Providence Saint John’s Health Center in Santa Monica, CA, spoke with MNT. She explained that future studies will be necessary to characterize “the immune system response and how to booster CD8+ and NK cells in order to give the children a more robust response to [SARS-CoV-2] infection and prevent MIS-C from occurring.”

Dr. Beckmann told MNT, “Our findings open new avenues for the understanding of the mechanisms [involved in] MIS-C, as well as new targets for drug and biomarker development.”

While explaining the implications of the findings to MNT, Dr. David Shafran, head of pediatrics at K Health, who was not involved in the study, said:

“This study specifically seeks to identify the underlying molecular cause of MIS-C. By understanding the cause of the ‘hyperinflammatory’ state of MIS-C to the level of its genetic basis, the genetic regulators of the immune dysfunction can become targets of treatment.”

Commenting on the limitations of the study, Dr. Fisher said: “This study was a retrospective review of inflammatory markers in children with MIS-C, with a very small number of children studied. This minimizes the power of the study, and it would be important to look at larger numbers of children with MIS-C in future studies.”